title: HIF1A reduces acute lung injury by optimizing carbohydrate metabolism in the alveolar epithelium.
abstract: BACKGROUND
  While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. Therefore, we hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection.
  
  
  RESULTS
  To examine transcriptional responses during ALI, we exposed pulmonary epithelia to cyclic mechanical stretch conditions--an in vitro model resembling mechanical ventilation. A genome-wide screen revealed a transcriptional response similar to hypoxia signaling. Surprisingly, we found that stabilization of hypoxia-inducible factor 1A (HIF1A) during stretch conditions in vitro or during ventilator-induced ALI in vivo occurs under normoxic conditions. Extension of these findings identified a functional role for stretch-induced inhibition of succinate dehydrogenase (SDH) in mediating normoxic HIF1A stabilization, concomitant increases in glycolytic capacity, and improved tricarboxylic acid (TCA) cycle function. Pharmacologic studies with HIF activator or inhibitor treatment implicated HIF1A-stabilization in attenuating pulmonary edema and lung inflammation during ALI in vivo. Systematic deletion of HIF1A in the lungs, endothelia, myeloid cells, or pulmonary epithelia linked these findings to alveolar-epithelial HIF1A. In vivo analysis of ¹³C-glucose metabolites utilizing liquid-chromatography tandem mass-spectrometry demonstrated that increases in glycolytic capacity, improvement of mitochondrial respiration, and concomitant attenuation of lung inflammation during ALI were specific for alveolar-epithelial expressed HIF1A.
  
  
  CONCLUSIONS
  These studies reveal a surprising role for HIF1A in lung protection during ALI, where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation.
authors.affiliation: Organ Protection Program, Department of Anesthesiology, University of Colorado School of Medicine, Denver, Colorado, United States of America.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eckle
authors.forename: Kelley
authors.initials: K
authors.lastname: Brodsky
authors.forename: Megan
authors.initials: M
authors.lastname: Bonney
authors.forename: Thomas
authors.initials: T
authors.lastname: Packard
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Borchers
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mariani
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kominsky
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D055371:Acute Lung Injury / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D050260:Carbohydrate Metabolism; D002460:Cell Line; D019069:Cell Respiration; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011654:Pulmonary Edema / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism*; D015398:Signal Transduction; D013385:Succinate Dehydrogenase / Q000378:metabolism
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; D013385:Succinate Dehydrogenase